K02 Independent Scientist Career Development Award for Joseph F. Cubells,MD, PhD This proposal seeks support for the candidate's continued development as a research psychiatrist specializing in human genetics of drug-abuse-related phenotypes. The overarching hypothesis organizing both the Research Plan and the Career Plan is that sequence variation at specific loci will exert measurable effects on specific drug-abuse-related phenotypes. This hypothesis is predicated on the importance of identifying and characterizing appropriate phenotypes, which will reflect the effects of one or a few genes with high penetrance. Three projects are proposed in the Research Plan. Project 1, which is well under way, is the candidate's R01-funded research on the human genetics of cocaine-induced psychosis (DA 12422). The project seeks to collect DNA samples from unrelated individuals with cocaine dependence, and from family trios containing cocaine-dependent probands; these probands are carefully characterized for cocaine-induced psychotic symptoms, and for axis-1 substance-abuse and psychiatric diagnoses, as well as for plasma levels of the catecholamine-synthetic enzyme dopamine beta-hydroxylase. Project 2 will build on work accomplished in Project 1, to examine how linkage disequilbrium among nearby polymorphisms influences phenotypic variation in quantitative traits. Project 3 will elucidate genetic influences on nicotine-dependence-related phenotypes by examining the influence of functional variation at the COMT locus on human neurocognitive function and acoustic startle responses in smoking and nonsmoking subjects, with and without schizophrenia. The Career Development Plan will entail collaboration with colleagues at Yale University and the University of Connecticut, whose expertises range from evaluation of complex phenotypes, to molecular genetics, to statistical genetics. In addition, the candidate plans specific coursework, both at Yale, and at off-campus sites, to strengthen his expertise in a both molecular, statistical and clinical genetics. The latter goal will be accomplished by the candidate directing the newly-established Yale Human Behavioral Genetics Clinic, which offers psychiatric and substance-abuse services to patients with genetic illnesses.